rs73569592

chr8-43197696-A-Cchr8-43197696-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_152419.3(HGSNAT):c.1567A>C(p.Lys523Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00608 in 1,613,202 control chromosomes in the GnomAD database, including 550 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (305 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (245 hom.)
• Consequence: HGSNAT NM_152419.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 4.17

Genes affected

HGSNAT (HGNC:26527): (heparan-alpha-glucosaminide N-acetyltransferase) This gene encodes a lysosomal acetyltransferase, which is one of several enzymes involved in the lysosomal degradation of heparin sulfate. Mutations in this gene are associated with Sanfilippo syndrome C, one type of the lysosomal storage disease mucopolysaccaridosis III, which results from impaired degradation of heparan sulfate. [provided by RefSeq, Jan 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025150776).
• BP6: Variant 8-43197696-A-C is Benign according to our data. Variant chr8-43197696-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 363150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-43197696-A-C is described in Lovd as [Benign]. Variant chr8-43197696-A-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.115 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HGSNAT	NM_152419.3	c.1567A>C	p.Lys523Gln	missense_variant	16/18	ENST00000379644.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HGSNAT	ENST00000379644.9	c.1567A>C	p.Lys523Gln	missense_variant	16/18	2	NM_152419.3	P3
HGSNAT	ENST00000519705.1	n.883A>C		non_coding_transcript_exon_variant	2/4	1
HGSNAT	ENST00000521576.1	c.718A>C	p.Lys240Gln	missense_variant	7/9	2		A2
HGSNAT	ENST00000523989.1	n.1880A>C		non_coding_transcript_exon_variant	1/2	4

Frequencies

GnomAD3 genomes AF: 0.0335 AC: 5096 AN: 152090 Hom.: 304 Cov.: 32

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00982

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.0172

GnomAD3 exomes AF: 0.00856 AC: 2134 AN: 249284 Hom.: 107 AF XY: 0.00656 AC XY: 887 AN XY: 135234

Gnomad AFR exome AF: 0.124

Gnomad AMR exome AF: 0.00461

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.00446

GnomAD4 exome AF: 0.00322 AC: 4706 AN: 1460994 Hom.: 245 Cov.: 30 AF XY: 0.00276 AC XY: 2006 AN XY: 726858

Gnomad4 AFR exome AF: 0.119

Gnomad4 AMR exome AF: 0.00521

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000909

Gnomad4 OTH exome AF: 0.00641

GnomAD4 genome AF: 0.0335 AC: 5104 AN: 152208 Hom.: 305 Cov.: 32 AF XY: 0.0328 AC XY: 2441 AN XY: 74434

Gnomad4 AFR AF: 0.118

Gnomad4 AMR AF: 0.00981

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.0170

Alfa AF: 0.00530 Hom.: 72

Bravo AF: 0.0372

ESP6500AA AF: 0.114 AC: 418

ESP6500EA AF: 0.000245 AC: 2

ExAC AF: 0.0106 AC: 1284

Asia WGS AF: 0.00346 AC: 13 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 11, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 05, 2017	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2018	This variant is associated with the following publications: (PMID: 17033958, 21228398, 19823584, 20981092, 19479962, 20583299) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 21, 2017	- -

Mucopolysaccharidosis, MPS-III-C Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Mucopolysaccharidosis, MPS-III-C;C4225287:Retinitis pigmentosa 73 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.22
Cadd	Uncertain	25
Dann	Benign	0.96
Eigen	Benign	0.13
Eigen_PC	Benign	0.036
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.80	T;T
MetaRNN	Benign	0.0025	T;T
MetaSVM	Benign	-0.88	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.6	N;N
REVEL	Uncertain	0.45
Sift	Benign	0.066	T;T
Sift4G	Benign	0.43	T;T
Vest4		0.42
MPC		0.15
ClinPred		0.035	T
GERP RS		4.3
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.32		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs73569592; hg19: chr8-43052839;